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International Journal of Antimicrobial Agents 38 (2011) 192– 196

Contents lists available at ScienceDirect

International Journal of Antimicrobial Agents

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eview

aptomycin: evaluation of a high-dose treatment strategy

ary Wu ∗, Teena Abraham, Jonathan Rapp, Fabienne Vastey, Nasser Saad, Eric Balmirew York Methodist Hospital, Department of Pharmacy, 506 6th Street, Brooklyn, NY 11215, USA

r t i c l e i n f o

eywords:aptomycinigh-dose daptomycinipopeptidentibiotic resistance

a b s t r a c t

With a decreasing pipeline of novel antibiotics and increasing antibacterial resistance, the need to opti-mise the current antibiotics in our armamentarium has become vitally important. Daptomycin is a novellipopeptide antibiotic that exhibits concentration-dependent activity. Currently, the daptomycin dosageis 4 mg/kg/day for treatment of complicated skin and soft-tissue infections and 6 mg/kg/day for Staphy-lococcus aureus bloodstream infections, including those with right-sided endocarditis, however higherdoses (>6 mg/kg/day) have been explored as a possible alternative. A comprehensive review of publisheddata identified through a MEDLINE search of the literature from 1967–2011 and a manual search ofreferences was performed with the primary objective of critically evaluating the safety and efficacy of

high-dose daptomycin. Search results yielded two prospective trials, three retrospective reviews, casereports and in vitro simulation studies on high-dose daptomycin. To date, clinical trials, retrospectivereviews, case reports and in vitro simulation models have documented the safety and tolerability ofhigh-dose daptomycin, even when administered for a prolonged duration. Additionally, in vitro bene-fits observed include suppression of the emergence of daptomycin resistance and increased rapidity ofbactericidal activity.

Publ

. Introduction

Treating antibiotic-resistant Gram-positive bacteria continueso be a challenge despite the development of new therapeuticptions [1]. Although vancomycin has been the gold standardor treatment of resistant Gram-positive pathogens, resistance isncreasing [1]. In a surveillance study of 50 US medical centres, therevalence of vancomycin-resistant enterococci (VRE) was 27.3%2]. Whilst vancomycin continues to be the mainstay for treatmentf meticillin-resistant Staphylococcus aureus (MRSA), increased fail-res have been described in isolates with a high vancomycininimum inhibitory concentration (MIC) (1–2 �g/mL) even when

eported as susceptible [3,4]. With most institutions across the USAaving rates of MRSA that have increased beyond 50%, this trend isxtremely worrisome [1]. One of the available alternatives to van-omycin therapy that has demonstrated in vitro and in vivo activitygainst MRSA and VRE is daptomycin [5,6].

Daptomycin is a novel lipopeptide antibiotic that possessesotent in vitro bactericidal activity against most clinically relevanttrains of Gram-positive bacteria, including resistant strains such

s MRSA and VRE [6,7]. Currently, daptomycin is indicated for thereatment of complicated skin and soft-tissue infections caused byusceptible organisms as well as S. aureus bloodstream infections

∗ Corresponding author. Tel.: +1 718 839 3596; fax: +1 718 780 3158.E-mail address: gary.wu2@gmail.com (G. Wu).

924-8579/$ – see front matter. Published by Elsevier B.V. on behalf of International Socioi:10.1016/j.ijantimicag.2011.03.006

ished by Elsevier B.V. on behalf of International Society of Chemotherapy.

(BSIs), including those with right-sided endocarditis [8]. Unfor-tunately, clinical failures and resistant strains have already beenreported with daptomycin [9–11]. Consequently, doses greaterthan the approved dosing are being considered as an alterna-tive (Table 1) [5,12–20]. Higher doses may take advantage of thepharmacokinetic (PK) profile of daptomycin and its concentration-dependent activity [12]. Although clinical experience with doses>6 mg/kg/day is limited, it has been increasingly utilised andhas been shown to be safe and well tolerated at doses up to12 mg/kg/day in healthy volunteers [12]. To our knowledge, a com-prehensive review of available clinical trials focusing on high-dosedaptomycin (>6 mg/kg/day) has not been published. Therefore, thisreview examines the safety and efficacy of high-dose daptomycin.

2. History of development

In the early 1980s, daptomycin, a fermentation product of Strep-tomyces roseosporus, was discovered at Eli Lilly and Company [21].However, there were concerns regarding skeletal muscle toxicityobserved even at dosages as low as 6 mg/kg/day in divided doses[22]. These concerns led to voluntary suspension of clinical trialsin 1991 [22]. In 1997, Cubist Pharmaceuticals licensed the world-wide rights to daptomycin, stemming from the increased need for

newer agents against Gram-positive pathogens [21]. This was fol-lowed by initiation of clinical trials in 1999 [22]. Ultimately, this ledto approval of daptomycin by the US Food and Drug Administration(FDA) in 2003 at single daily doses of 4 mg/kg for the treatment

ety of Chemotherapy.

G. Wu et al. / International Journal of Antimicrobial Agents 38 (2011) 192– 196 193

Table 1Summary of high-dose daptomycin clinical and retrospective studies.

Trial design (daptomycin regimen) Patient population Primary clinical findings Comments

Prospective designSingle-centre, randomised,double-blinded, phase 1 study(6–12 mg/kg/day) [12]

36 healthy volunteers No subjects reported myalgia; CPK assessmentswere within normal limits for all treatment groups

Safety and tolerability ofdaptomycin at doses up to12 mg/kg/day for 14 daysdemonstrated

Multicentre, randomised,active-controlled trial(10 mg/kg/day) [13]

96 patients with cSSSI due toGram-positive pathogen

CPK increase in 4 (8.3%) of 48 patients treated withdaptomycin versus 0 (0%) of 48 patients incomparator group (P-value not reported)a. DuringTOC assessment, clinical success achieved in 36/48patients (75.0%) treated with HDSD daptomycinand 42/48 patients (87.5%) in the comparatorgroup (95% CI for the difference –27.9% to 2.9%)

A HDSD daptomycin regimen wasrelatively safe and well tolerated.Although not statisticallysignificant, HDSD daptomycinexhibited lower rates of clinicalsuccess

Retrospective designRetrospective chart review(>6 mg/kg/dose) [14]

61 patients treated withdaptomycin >6 mg/kg/dose for ≥14days

Amongst 47 patients with paired CPK analysis or atrandom during treatment, 3/47 (6.4%) developedsignificant CPK elevations >1000 U/L withcomplaints of constitutional and/ormusculoskeletal symptoms. Symptoms resolvedwith discontinuation of therapy

Incidence of significant CPKelevation is similar to thosepreviously reported with shortercourses or lower doses ofdaptomycin

Retrospective chart review(≥8 mg/kg/dose) [5]

94 patients treated withdaptomycin ≥8 mg/kg/dose

3 (3.2%) of 94 patients experienced CPK elevations.In the clinically evaluable population, clinicalsuccess was achieved in 66 (89%) of 74 patients

Daptomycin ≥8 mg/kg/dose wasefficacious and well tolerated

Retrospective chart review(>6 mg/kg/day and≤6 mg/kg/day) [15]

53 patients with Staphylococcusaureus infections

Clinical success was achieved in 29/31 patients(94%) in the high-dose treatment group comparedwith 16/22 patients (73%) in the standard-dosegroup (P = 0.05); microbiological success wasachieved in 27/29 patients (93%) in the high-dosetreatment group and 13/19 patients (68%) in thestandard-dose group (P < 0.05)

High-dose daptomycindemonstrated an increasedlikelihood of microbiologicalsuccess

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PK, creatine phosphokinase; cSSSI, complicated skin and skin-structure infection;a Comparator regimen was vancomycin 1 g intravenous every 12 h for up to 14 d

f complicated skin and skin-structure infections (cSSSIs) causedy susceptible strains, and in 2006 at 6 mg/kg for S. aureus BSIs,

ncluding those with right-sided endocarditis [8,23].

. Microbiology and mechanism of action

The mechanism of action of daptomycin is distinct from any cur-ently available antibiotics [1]. By binding to bacterial membranes,aptomycin causes channel formation within the cell wall, enablinghe efflux of potassium with rapid depolarisation of the mem-rane potential [1,8]. Subsequently, this loss of membrane potential

eads to inhibition of protein, DNA and RNA synthesis, causingacterial cell death [8]. Daptomycin is effective against most Gram-ositive pathogens, including those with multidrug resistance8,22]. Multidrug-resistant organisms in which daptomycin hashown in vitro activity include MRSA, glycopeptide-intermediate. aureus (GISA), vancomycin-resistant S. aureus (VRSA) and VRE6,24]. It is important to note, however, that concerns have beenaised regarding the use of daptomycin in patients previouslyreated with vancomycin, citing the potential for reduced suscepti-ility, although a comprehensive discussion of this topic is beyondhe scope of this review [10,25].

. Pharmacokinetics and pharmacodynamics

Daptomycin exhibits concentration-dependent activity ratherhan time-dependent activity (time the drug concentration exceedshe MIC) [26]. Therefore, the parameters that best correlate with the

fficacy of daptomycin are its peak concentration (Cmax) or areander the concentration–time curve from 0–24 h (AUC0–24) [26].ollowing intravenous (i.v.) administration, daptomycin exhibitsenerally linear pharmacokinetics at doses of 4–12 mg/kg every

est of cure; HDSD, high-dose short-duration; CI, confidence interval.itch to semisynthetic penicillin permitted based on susceptibility profile.

24 h (q24h) [8]. Based on the PK and pharmacodynamic (PD) prop-erties of daptomycin, some practitioners are using high doses ofdaptomycin routinely in the hope of maximising efficacy [17].

5. High-dose daptomycin

5.1. Prospective studies

5.1.1. Phase 1 studyIn a single-centre, randomised, double-blinded, placebo-

controlled phase 1 study involving 36 healthy volunteers, the safetyand tolerability of daptomycin was studied up to 12 mg/kg/day for14 days [12]. The primary objective of this study was to examine thePK profile from the dosage range of 6–12 mg/kg once daily, whilstthe secondary objective was to evaluate safety and tolerability of a10 mg/kg and 12 mg/kg once-daily regimen for 14 days. Study par-ticipants were randomised to three cohorts. Each cohort consistedof 12 patients. Cohort 1 assigned healthy volunteers at a 3:1 ratioto receive daptomycin 10 mg/kg once daily or placebo for 14 days.Cohort 2 also randomised healthy volunteers at a 3:1 ratio to receivedaptomycin 12 mg/kg once daily or placebo for 14 days. Finally,cohort 3 assigned the study participants in a 1:1 ratio to receivedaptomycin 6 mg/kg or 8 mg/kg once daily for 4 days with the goalof determining the PK baseline in order to enable comparison withhigher daptomycin doses. In cohorts 1 and 2, creatine phospho-kinase (CPK) was measured at baseline and on Days 4, 7 and 14 aswell as Day 3 post treatment. For cohort 3, CPK measurements wereperformed at baseline and on Day 4. The study participants did not

experience any adverse events during the study that were seriousor led to discontinuation of treatment.

Adverse events were reported in the majority of patients incohorts 1 and 2, including nine (100%) of nine patients in the

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0 mg/kg group, seven (78%) of nine patients in the 12 mg/kg groupnd five (83%) of six patients in the placebo groups. When combin-ng the 10 mg/kg group and the 12 mg/kg group, the most frequentdverse events reported in 18 patients were headache in 5 patients27.8%), adenoviral upper respiratory infection in 4 patients (22.2%),onstipation in 2 patients (11.1%), arthralgia in 2 patients (11.1%),phthous stomatitis in 2 patients (11.1%) and urinary tract infec-ion (UTI) in 2 patients (11.1%). However, excluding arthralgia andTI, these adverse effects were also reported in one or more of thelacebo subjects. Remarkably, no subjects reported myalgia duringhe study, and CPK assessments were within normal limits for allreatment groups.

This phase 1 study demonstrated the safety and tolerability ofigh-dose daptomycin in doses up to 12 mg/kg in healthy studyarticipants over a 2-week period and provided support for further

nvestigation of high-dose daptomycin especially in infections thatre difficult to treat.

.1.2. High-dose, short-duration (HDSD) daptomycinA HDSD regimen of daptomycin was studied in a prospective,

ulticentre, randomised, active-controlled study involving 100atients [13]. This study evaluated the efficacy and safety of dap-omycin at 10 mg/kg/q24h for 4 days compared with vancomycin

g i.v. every 12 h for up to 14 days. A switch to semisyntheticenicillin 2 g i.v. every 4 h in patients initially treated with van-omycin was an option if infection was later found to be due to

meticillin-sensitive Gram-positive organism. The investigatorshose this dosage regimen because it provides the same total drugxposure as 10 days of the 4 mg/kg dose. The objective of this studyas to provide initial data on the safety and efficacy of this dapto-ycin dosage regimen in order to generate hypotheses to be tested

n future clinical investigations. Inclusion criteria for this studyere patients ≥18 years of age, creatinine clearance ≥50 mL/min,ith a documented cSSSI and infection due to, at least in part,

Gram-positive pathogen. Patients were evaluated at the end ofherapy (EOT) evaluation and for a test of cure (TOC) 7–14 days fol-owing completion of antimicrobial therapy. CPK was monitored ataseline and on Days 3 and 5/6. At EOT, clinical success, defineds cure or clinical improvement, was achieved in 40/48 patients83.3%) treated with daptomycin and 44/48 patients (91.7%) treatedith the comparator regimen [95% confidence interval for theifference (CI)–21.5% to 4.8%]. At TOC assessment, success ratesere 36/48 patients (75.0%) treated with HDSD daptomycin and

2/48 patients (87.5%) treated with the comparator regimen (95%I for the difference −27.9% to 2.9%). Adverse events that were

udged to be treatment-related occurred more frequently in theaptomycin treatment group (20/48; 41.7%) compared with theomparator group (11/48; 22.9%) (P = 0.08). Specifically, adversevents judged to be treatment-related in the daptomycin grouphat occurred most commonly included nausea in 4 (8.3%) of 48atients and blood CPK increase in 4 (8.3%) of 48 patients, whilst

n the comparator group nausea occurred in 2 (4.2%) of 48 patientsnd blood CPK increase in 0 of 48 patients, respectively (P-valueot reported). Amongst the four patients who had elevations inPK that were daptomycin treatment-related, three patients had

ncreases to >500 U/L and complaints of myalgia. Importantly, nonef the adverse effects that patients in the daptomycin treatmentrm experienced were deemed as serious. More patients in theomparator arm received surgical procedures such as incision andrainage and/or wound debridement, which may be secondaryo increased opportunities for surgical interventions from longeruration of i.v. treatment. The adjunctive surgical procedures were

erformed in 7 (14.6%) of 48 patients and in 12 (25.0%) of 48 patients

n the daptomycin and comparator arms, respectively (P-value noteported). Limitations of this study included a lack of statisticalower to detect difference between treatment groups, unblinded

icrobial Agents 38 (2011) 192– 196

study investigators and imbalanced frequency of adjunctive surgi-cal procedures.

Despite a lack of statistical significance, this study raises efficacyconcerns for a HDSD daptomycin treatment regimen because oflower clinical success rates. However, this study adds to the increas-ing evidence of the safety and tolerability of high-dose daptomycinas no serious adverse events were observed.

5.2. Retrospective studies

5.2.1. Case seriesAt New York Hospital Queens (Flushing, NY), a retrospective

chart review was performed for all patients treated with high-dosedaptomycin from 1 January 2004 to 30 April 2007 [14]. The goalof the chart review was to describe the safety of high-dose dap-tomycin (>6 mg/kg/dose) for treatment courses of ≥14 days. Theefficacy of high-dose daptomycin was not reported in this study. Acomputerised hospital pharmacy database facilitated the identifi-cation of patients who met the inclusion criteria.

The inclusion criteria were satisfied in 61 patients. Adverseevents as documented in the medical record were compared withthose reported in a randomised study of daptomycin for BSI [27]as well as the package insert [8]. Increases in serum CPK valuesthat were considered significant were those that elevated to 10-fold greater than the upper limit of normal regardless of whetherthe patient was symptomatic. The mean dose in patients who wereanalysed was 8 mg/kg (range 7–11 mg/kg); length of treatment wasa median of 25 days (range 14–82 days). The investigators reportedthat 22 (36.1%) of 61 patients experienced mild adverse events (e.g.diarrhoea, nausea and arthralgia) that did not require daptomycinto be discontinued. In the 47 patients who had any CPK analysis(either paired at the beginning of and during therapy or at randomduring treatment), a significant CPK elevation was observed in 3patients (6.4%). All three patients developed serum CPK elevations>1000 U/L and all were symptomatic with complaints of consti-tutional and/or musculoskeletal symptoms following 24–28 daysof treatment. Therapy with daptomycin was discontinued in thesethree patients, leading to resolution of symptoms. The investigatorsnote that the incidence of significant serum CPK elevation was sim-ilar to those previously reported when shorter courses of treatmentand/or lower doses of daptomycin were utilised. In clinical studies,significant increases in CPK have occurred in 2.5–8.3% of patients.An analysis of treatment outcomes is planned. Limitations of thisstudy include its retrospective design, small sample size, variabledosing, and incomplete and inconsistent serum CPK analysis. How-ever, the investigators concluded that high-dose daptomycin at amean of 8 mg/kg/dose for a median duration of 25 days was welltolerated.

This retrospective analysis demonstrated the tolerability ofhigh-dose daptomycin for a median duration of 25 days, with nodramatic increases in serum CPK elevation compared with previ-ously published clinical studies.

5.2.2. Retrospective observational chart reviewsThe safety and efficacy of daptomycin ≥8 mg/kg was evaluated

and analysed from data collected as part of the Cubicin® OutcomesRegistry and Experience (CORE) database, which is a multicen-tre, retrospective, observational study [5]. Patients of all ages andany dose or duration of therapy were eligible for inclusion in theCORE database. The database contains information on demograph-ics, treatments, infections and outcomes for patients treated withdaptomycin at the conclusion of therapy. Patients who were eli-

gible for safety assessments include all patients having receivedat least one daptomycin dose of ≥8 mg/kg. Efficacy of treatmentswas assessed only in an evaluable population, whereas a patientwhose infection response was not recorded or did not contain

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dequate information was not evaluated. Ninety-four patients fromhe CORE database met the criteria of receiving daptomycin at aose of ≥8 mg/kg. One adverse event or abnormal laboratory resultas reported in 28 (30%) of 94 patients, of which 6 (6.4%) of 94atients had adverse events assessed as possibly related to treat-ent with daptomycin. Amongst the six patients who had possible

aptomycin-related adverse events, three experienced CPK eleva-ions. All CPK increases were assessed and deemed as non-serious.n the efficacy analysis, 20 cases were excluded because they wereudged to be non-evaluable. As for the remaining population, clini-al success (clinical cure or improvement) was achieved in 66 (89%)f 74 patients.

Notably, a significantly lower clinical success rate (8/12; 67%)as reported with endocarditis when judged against the other

nfections (P = 0.006). Comparatively, a positive clinical responseccurred in 20 (91%) of 22 bacteraemias and 15 (88%) of 17 SSSIs.he median duration of high-dose daptomycin therapy in theatients analysed was 15 days (range 1–90 days). Limitations ofhis study include its retrospective, uncontrolled, non-randomised,nblinded design. Also, there may have been a falsely elevated clin-

cal success rate because patients’ follow-up data had not beenollected, therefore the potential for relapse exists. Furthermore,icrobiological cure had not been assessed as cultures were not

equired at the end of therapy. However, based on the studyutcomes, daptomycin doses of ≥8 mg/kg were efficacious andell-tolerated even when given over an extended period.

Another retrospective chart review was conducted comparingtandard-dose daptomycin (≤6 mg/kg/day) with high-dose dapto-ycin (>6 mg/kg/day) in patients with staphylococcal infections

15]. Patients included in the analysis were treated for a minimumf 10 days with daptomycin. In total, 53 patients were identified,f which 22 were treated with standard-dose daptomycin versus1 patients in the high-dose treatment group. Amongst the staphy-

ococcal infections, 19 (86%) of 22 in the standard-dose treatmentroup versus 27 (87%) of 31 in the high-dose treatment group wereRSA. In the standard-dose daptomycin treatment group, 16 (73%)

f 22 patients had documented clinical success compared with 2994%) of 31 patients in the high-dose treatment group (P = 0.05).

icrobiological success was achieved in 13 (68%) of 19 patients inhe standard-dose group and in 27 (93%) of 29 patients in the high-ose treatment group (P < 0.05). CPK was elevated in one patient3.2%) treated with high-dose daptomycin to >1000 U/L, with lev-ls returning to normal range within 1 week once treatment wasiscontinued. Incidences of other adverse events were similar inoth groups, with mild adverse events (i.e. anaemia, diarrhoea,rthralgia) occurring in 9% of patients treated with the standardose and 9.7% treated with the high-dose regimen, none of whichequired the discontinuation of daptomycin therapy. The studyesults demonstrated the safety and possible increased efficacyith high-dose daptomycin compared with standard-dose dap-

omycin. However, it is important to note that the duration ofherapy for patients in the high-dose treatment group was 19 daysompared with 13.5 days in the standard-dose treatment groupP < 0.02), which is a potential limitation of the study. Additionalimitations include a small sample size and its retrospective nature.

. Case reports

Multiple cases of patients treated with high-dose daptomycinave also been reported in the literature [16–20]. Some investiga-ors have attributed clinical success to the increased daptomycin

osage [16,20] Doses between 8 mg/kg/q24 and 12 mg/kg/q24ave been utilised for the treatment of acute bacterial MRSAndocarditis, MRSA bacteraemia, vancomycin-resistant Enterococ-us faecium endocarditis and prosthetic infections for prolonged

icrobial Agents 38 (2011) 192– 196 195

periods [16,17,19,20]. In these reports, the patients did not experi-ence adverse events or CPK elevations as a result of the high-doseregimens [16–20]. These case reports provide further evidence insupport of clinical benefit without increased toxicities when utilis-ing a high-dose daptomycin treatment strategy.

7. In vitro simulation models

The impact of high-dose daptomycin has also been demon-strated in in vitro simulation models [28,29]. In a simulatedendocardial vegetations (SEV) model, the activity of 10 mg/kg/q24hdaptomycin in a daptomycin-susceptible MRSA isolate (SA-675)and a daptomycin-reduced-susceptibility MRSA isolate (SA-684)was compared with a 6 mg/kg/q24h daptomycin regimen [29].The parameters evaluated included rapidity of bactericidal activity[initial inocula reduced by ≥3 log10 colony-forming units (CFU)/g]via time to 99% kill (T99.9) and changes in CFU/g up to 96 h [29].For SA-675, T99.9 was achieved in 2.7 h with the 10 mg/kg reg-imen versus 14.1 h with the 6 mg/kg regimen [29]. For SA-684,T99.9 was attained in 5.4 h with the 10 mg/kg regimen versus 25.6 hwith the 6 mg/kg regimen [29]. Unlike the activity of daptomycin6 mg/kg/q24h against SA-675, reduced activity and re-growth wasobserved in SA-684 [29]. Comparatively, the 10 mg/kg/q24h regi-men in SA-675 achieved a reduction in initial inoculum to detectionlimits (2 log10 CFU/g) faster than the 6 mg/kg regimen (24 h vs. 72 h,respectively), and in SA-684 the decrease in initial inoculum todetection limits occurred by 32 h with minimal re-growth [29]. Inanother SEV model, emergence of reduced susceptibility to dapto-mycin was seen in S. aureus isolates tested with the 6 mg/kg/q24hregimen, observing up to a three-fold increase in MIC [28]. Thisobservation was suppressed with the 10 mg/kg/q24h regimen [28].

These in vitro simulation models demonstrate that increasingthe dose of daptomycin beyond the currently highest approveddose (6 mg/kg/q24h) may decrease the time to bactericidal activityin addition to suppressing the emergence of reduced daptomycinsusceptibility in S. aureus isolates.

8. Conclusion

The current literature on a high-dose daptomycin treatmentstrategy suggests safety and tolerability, even when given forextended durations, along with improved in vitro efficacy. How-ever, evidence in support of improved in vivo efficacy fromrandomised, prospective clinical trials in large populations is stilllacking, but necessary. With the optimum dose of daptomycinstill unknown, perhaps the most appropriate situations to utilisehigh-dose daptomycin are in difficult-to-treat infections such asendocarditis.

Funding: No funding sources.Competing interests: None declared.Ethical approval: Not required.

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